Gold(I)-catalyzed intramolecular [4+3]-cycloaddition reactions with furan propargyl esters as the substrates: Carbenoid vsstabilized allyl cation

Article abstract of DOI:10.1055/s-0033-1338946

The tricyclic ring system with an oxabicyclo[3.2.1]octadiene and a fused six-membered ring was produced efficiently using the readily available propargyl ester furan substrate in the presence of a Au(I) complex. The reaction involves a tandem 3,3-rearrangement of the propargyl ester followed by an intramolecular [4+3]-cycloaddition reaction. Both the primary ligand of the gold complex (N-heterocyclic carbene; NHC) and a neutral dynamic ligand (PhCN) are important for the success of the reaction. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338946

1238▌
CLUSTER
cluster
Gold(I)-Catalyzed Intramolecular [4+3]-Cycloaddition Reactions with Furan
Propargyl Esters as the Substrates: Carbenoid vs. Stabilized Allyl Cation
Gold(I)-Catalyzed Intramolecular [4+3]-Cycloaddition Reaction
Benjamin W. Gung,* Ryan C. Conyers, Josh Wonser
Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio 45056, USA
Fax +1(513)5295715; E-mail: gungbw@muohio.edu
Received: 02.04.2013; Accepted after revision: 22.04.2013
cyclo[3.2.1]octane core structures could also be obtained
Abstract: The tricyclic ring system with an oxabicyclo[3.2.1]octa-
by using the Au(I)-catalyzed tandem 3,3-rearrange-
diene and a fused six-membered ring was produced efficiently using
ment/intramolecular [4+3]-cycloaddition of the furan
propargyl esters.
the readily available propargyl ester furan substrate in the presence
of a Au(I) complex. The reaction involves a tandem 3,3-rearrange-
ment of the propargyl ester followed by an intramolecular [4+3]-cy-
cloaddition reaction. Both the primary ligand of the gold complex
(N-heterocyclic carbene; NHC) and a neutral dynamic ligand
(PhCN) are important for the success of the reaction.
Propargyl esters have been shown to rearrange to either a
gold carbenoid or an acetoxyallene in the presence of a
gold complex through a 1,2- or 1,3-shift of the ester
group.7,8 The two reaction pathways are proposed to be
competitive, and that the key intermediates in rapid equi-
librium. We previously reported successful transannular
[4+3]-cycloaddition reactions with the furan propargyl es-
ter precursors.3 However, in the study of intermolecular
reactions, we observed that internal propargyl esters pref-
erentially rearrange to α-ylidene-β-diketones in the pres-
ence of gold complexes, rather than the anticipated [4+3]-
cycloaddition with furan. Zhang and co-workers have re-
ported this rearrangement without the presence of furan.9
Recently, new rearrangements of propargylic esters have
been reported.10
Key words: gold-catalyzed, cycloadditions, furan, propargyl ester,
carbenoid
Our interest in applying a transannular [4+3]-cycloaddi-
tion reaction to obtain the core structure of the potent
anticancer agent cortistatin A (Figure 1)1 led us to inves-
tigate the Au(I)-catalyzed cycloadditions with furan
propargyl esters as the precursors.2,3 To expand the scope
of this method, we have studied the intramolecular ver-
sion of this reaction. In the last several years the arsenal of
new gold-catalyzed methods is increasingly applied in
organic synthesis.4
When dimethylfuran was allowed to react with terminal
propargyl esters in the presence of PicAuCl2 [dichloro(2-
pyridinecarboxylato)gold],11 a stepwise 1,2-ester shift and
cyclopropanation followed by furan ring-opening reaction
were observed (Scheme 1). Gold-catalyzed intermolecu-
lar reactions involving furans are very rare.12 Ohe and co-
workers have reported a similar ruthenium-catalyzed het-
erocycle opening reaction.13 A carbenoid intermediate
was reportedly involved and the mechanism of the gold-
catalyzed phenol synthesis involves such ring openings,
too.14
OH
HO
Ar
O
H
Me2N
cortistatin A (1)
Figure 1 Potent antiangiogenesis natural product, cortistatin A, fea-
turing a oxabicyclo[3.2.1]octene core structure fused with two six-
membered rings
Other recent studies of gold-catalyzed intramolecular
[4+3]- and [4+2]-cycloadditions involved the employ-
ment of preassembled allene dienes.5 It was demonstrated
that a selective [4+3] or [4+2] products could be achieved
by employing either Ar3PAu(I)- or (ArO)3PAu(I)-type of
catalysts. However there is still a lack of synthetic meth-
odologies that produce the desired 6-7 ring system with
the oxabicyclo[3.2.1]octane structure. A recent report on
an efficient synthesis of cortistatin J employed an intra-
molecular [4+3]-cycloaddition reaction with a furan func-
tional group adding to a (Z)-2-(trialkylsilyloxy)-2-enal
three-carbon moiety.6 This prompted us to show that the
desired 6-7 fused rings in combination with the oxabi-
O
OBz
OBz
PicAuCl2 (5%)
CH2Cl2, r.t.
[Au]
– [Au]
2
3
OBz
O
OBz
O
5
4
Scheme 1 Terminal propargyl ester 2 reacted with dimethylfuran in
the presence of a gold catalyst to give triene 5, most likely through the
carbenoid 3
SYNLETT 2013, 24, 1238–1242
Advanced online publication: 28.05.2013
DOI: 10.1055/s-0033-1338946; Art ID: ST-2013-R0297-C
© Georg Thieme Verlag Stuttgart · New York
The results from the intermolecular reactions are in con-
trast to our earlier successful transannular reactions.3 En-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

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Gold(I)-Catalyzed Intramolecular [4+3]-Cycloaddition Reaction
1239
tropic effects are considered to play a major role in the alcohol. The desired propargyl ester 12 was obtained by
difference in the two types of reactions. It was uncertain acylation of the resulting secondary alcohol in 80% yield
whether an intramolecular [4+3]-cycloaddition could be over two steps. Propargyl ester 16 was prepared starting
successfully carried out with gold-catalyzed furan propar- from 1-(4-bromobutyl)furan (13; Scheme 3).18 Substitu-
gyl esters.
tion reaction with lithiated THP protected propargyl alco-
hol gave 14 in 76% yield.
Previous computations have shown that for terminal
propargyl esters in the presence of a Au(I) catalyst, 1,2-
acyl migration has a lower barrier than 1,3-acyl migra-
tion.8 Since there is no report on computations of internal
propargyl esters, we performed a DFT calculation for the
prototype of substrate, such as 6 in Scheme 2, but with re-
alistic NHC ligand considering the importance of steric
effects. Our calculation shows that 1,3-migration of the
ester group is preferred by the internal propargyl ester 6.
Not only the six-membered intermediate 9 is energetically
favored over the five-membered intermediate 7, but also
the cationic allyl intermediate 10 is 5.4 kcal/mol more sta-
ble than the corresponding carbenoid intermediate 8.
These results indicate that internal propargyl esters should
provide a better chance for [4+3]-cycloaddition reactions.
Encouraged by the computational results, three substrates
with an internal triple bond were prepared for performing
the intramolecular [4+3]-cycloaddition reactions (Scheme
3).
AcO
O
1)
BuLi, THF
–78 °C to 0 °C
O
O
2) AcCl, pyridine
DMAP, CH2Cl2, 0 °C to r.t.
80% over 2 steps
11
12
O
OTHP
Br
OTHP
1) p-TsOH
MeOH, r.t.
BuLi, HMPA,
THF, –50 °C to r.t.
2) PCC, NaOAc
Celite, CH2Cl2
48% over 2 steps
O
O
O
76%
13
14
15
OAc
1) EtMgBr
0–5 °C, THF
2) AcCl, pyridine
DMAP, CH2Cl2, 0°C to r.t.
55% over 2 steps
O
L
L
Au
+Au
16
1) (COCl)2, DMSO, Et3N
THF, –78 °C to r.t.
2) –78 °C to –50 °C to 0 °C
+
O
O
O
O
O
Li
O
+
7 (+4.5)
8 (+10.0)
OAc
L
Au
O
6 (0.0)
O
O
O
O
+
+
17
O
4-penten-1-ol
3) AcCl, pyridine,
DMAP, CH2Cl2,
0 °C to r.t.
Au
L
10 (+4.6)
Au
L
9 (–1.0)
18
N
N
L =
48% over 3 steps
Scheme 3 Preparation of furan propargyl esters 12, 16, and 18
Scheme 2 Computations were performed on 1,2- vs. 1,3-migration
of the acetate group in the internal propargyl ester 6 to produce the
carbenoid specie 8 vs. the cationic 1,3-dipole 10. Relative to the L-Au
coordinated alkyne 6, the carbenoid 8 has a relative energy of 10
kcal/mol and the allyl cation 10 has an energy of 4.6 kcal/mol. The
Becke’s three parameter hybrid functional with the Lee–Yang–Parr
correlation functional was used.15 The 6-31G* basis set was used for
main group atoms,15 while the relativistic SDD effective core poten-
tial was used for the Au atom.16
After removal of the THP ether protecting group from 14
with TsOH in MeOH, PCC oxidation of the resulting pri-
mary alcohol produced aldehyde 15 in 48% yield. Nucleo-
philic addition to the aldehyde with ethyl magnesium
bromide followed by acylation afforded the desired
propargyl ester 16 in 55% yield over two steps. The syn-
thesis of propargyl ester 18 started with 4-pentenal
(Scheme 3). After allowing 4-pentenal to react with the
lithiated alkyne 17,19 acylation of the crude secondary al-
cohol gave the propargyl ester 18 in 48% yield over three
steps.
Substrates 12 and 16 were designed to study the effect of
the ester position on the connecting chain. Substrate 18
was aimed to test the carbenoid character of the reactive
intermediate by possible trapping of the carbenoid inter-
mediate with the terminal double bond. The synthesis of
propargyl ester 12 started with the known furan aldehyde
11 (Scheme 3),17 which was allowed to react with lithiated
1-pentyne to give the corresponding secondary propargyl
Once the propargyl esters were in hand a brief screening
of four gold complexes for the intramolecular [4+3]-
cycloaddition reaction was performed. The different gold
catalysts examined in this study are shown in Figure 2.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1238–1242

1240
B. W. Gung et al.
CLUSTER
i-Pr
i-Pr
i-Pr
t-Bu t-Bu
AuCl
F
F
F
P
+
N
N
O
N
F
P
AuCl
Cl Au
O
Au
i-Pr
F
Cl
3
Cl
19
20
21
22
Figure 2 Gold complexes screened in this study
Disappointing results were obtained with complexes 19– The observation of reactions of 12 producing two diaste-
21. In the presence of the electron-deficient gold complex reoisomers and 16 producing only one diastereomer can
19, substrate 16 yielded 17% of the bicyclic ketone 23.
be explained by considering the acetate location on the
connecting chain between furan and the triple bond. Our
suggested pathways are shown in Scheme 5. Initial Au(I)-
catalyzed 1,3-acetate migration in substrates 12 and 16
leads to acetoxyallenes A and F, respectively. The loca-
tion of the acetate is on the opposite end of the allene func-
tion in 12 and in 16. As the Au(I) catalyst activates the
acetoxyallene function into an allyl cation (B, C, G, or H),
the formation of the first bond between furan and the allyl
cation should be the one that forms a six-membered ring
such as those shown in Scheme 5. It is reasonable to sug-
gest that the energy difference between B and C is much
smaller than that between G and H because of the location
of the acetate group. Therefore, compounds 24 and 25
were both observed in the reaction of 12 and 26 was the
only isolated product of 16.
Compound 23 appears to be a secondary rearrangement
product from an initial intramolecular [4+3]-cycloaddi-
tion product 26. A similar ring-opening product was iso-
lated by us previously.20 Thus complex 19 appears to have
a strong Lewis acid character, which caused decomposi-
tion of the substrate and the generation of the secondary
reaction product. The gold complexes 20 and 21 were ef-
fective catalysts during our study of the transannular
[4+3]-cycloaddition reactions.3 In contrast, the reactions
with substrates 12, 16, and 18 were sluggish in the pres-
ence of complexes 20 and 21. Most of the starting materi-
als decomposed after stirring for prolonged time. Some
desired products (24) were observed with either complex
20 or 21. Unfortunately the yield was low even with up to
20 mol% of catalyst loading and reaction time of up to
four days. The best catalyst for the intramolecular [4+3]-
cycloaddition was the gold complex (IPr)Au(I)Cl 22. We
were pleased to observe when in the presence of
22/AgSbF6 mixture,21 the substrate 16 gave the desired
[4+3]-cycloaddition product in 70% yield with catalyst
loading at 10 mol% and a reaction time of five hours
(Scheme 4, equation 3). In the presence of (IPr)Au(I)Cl
(22)/AgSbF6, furan propargyl ester 12 gave a mixture of
two diastereomers 24 and 25 in 50% yield with a ratio of
2.3:1 in favor of 24 (Scheme 4, equation 2). Substrate 16
gave a single diastereomer 26 in 70% yield (Scheme 4,
equation 3). Substrate 18 with a terminal alkene produced
a mixture of two products in 93% combined yield with a
ratio of 5.2:1 in favor of the desired [4+3]-cycloaddition
product 27 (Scheme 4, equation 4). No interception of car-
benoid intermediate was observed with 18. However,
product 28 was isolated, which resulted from a direct
enyne cyclization without the migration of the acetate
group. This is a rather unique 1,6-enyne isomerization
product comparing to numerous previously reported sim-
ilar type of reactions in that compound 18 is an internal al-
kyne and the acetate group remained on the same carbon
after reaction.22
OAc
O
19 (20 mol%)
AgSbF6 (20 mol%)
(1)
CH2Cl2, r.t., 2.5 h
17%
OAc
Pr
O
23
16
OAc
OAc
O
H
H
22 (10 mol%)
Pr
AgSbF6 (10 mol%)
+
(2)
(3)
12
16
O
CH2Cl2, r.t., 5.5 h
50%
24
2.3:1
OAc
25
22 (10 mol%)
AgSbF6 (10 mol%)
O
CH2Cl2, r.t., 5.5 h
70%
26
OAc
OAc
O
22 (10 mol%)
AgSbF6 (10 mol%)
O
(4)
(5)
+
3
18
16
CH2Cl2, r.t., 5.5 h
93%
27
5.2:1
28
The formation of 27 should follow a similar pathway to
the formation of 26 from 16. The formation of 28 involves
an initial activation of the internal alkyne by the Au(I) cat-
alyst, which is followed by a nucleophilic attack by the
pendant alkene resulting in the formation of a gold car-
benoid species. The carbenoid intermediate undergoes a
1,2-hydride shift followed by elimination of AuL+ to af-
ford product 28.
OAc
(IMes)Au(I)·NCPh
30 (10 mol%)
23
+
O
CH2Cl2, 4 h, r.t.
89%
26
6.4:1
Scheme 4
Synlett 2013, 24, 1238–1242
© Georg Thieme Verlag Stuttgart · New York

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Gold(I)-Catalyzed Intramolecular [4+3]-Cycloaddition Reaction
1241
catalyst. The groups of Nolan25 and Echavarren have in-
dependently reported that a neutral ligand such as aceto-
nitrile and benzonitrile can further improve the gold
complex catalytic efficiency.26 We prepared such a gold
complex starting from the (IMes)Au(I)Cl (29)21 as shown
in Scheme 6.
AcO
+
AuL+
•
[Au]
[Au]
AuL+
O
12
B
OAc
O
1,3-acetate
migration
AcO
O
+
A
When the substrate propargyl ester 16 was treated with the
neutral gold complex 30 in CH2Cl2 at room temperature
for four hours, an 89% yield of a mixture of 26 and 23 was
obtained in a 6.4:1 ratio in favor of 26 (Scheme 4, equa-
tion 5), a better result than using 22 with AgSbF6. As de-
scribed above, compound 23 was formed as a secondary
reaction product from 26. The small amount of 23 isolated
when using complex 30 could be a result of the more Lew-
is acidic Au(III)-promoted ring opening of 26. Some min-
ute amount of Au(III) species might have been formed in
a disproportionation reaction of the complex 30. The
(IMes)Au(I) complex is not as sterically protected as the
(IPr)Au(I) complex. Hence it is easier to undergo dispro-
portionation to produce Au(III) and Au(0) species. This
study shows that the desired 6-7 fused rings plus the ox-
abicyclo[3.2.1]octane core structures can be obtained in
one operation by using the Au(I)-catalyzed tandem 3,3-re-
arrangement/intramolecular [4+3]-cycloaddition of the
furan propargyl esters.27 With continued improvement of
the NHC ligand and a dynamic co-ligand, Au(I) catalysts
should provide the most efficient route in the synthesis of
the tricyclic products. Work along these lines is underway
in our laboratories.
C
OAc
H
[Au]
[Au]
O
1,2-acetate
migration
D
25
24 +
OAc
deauration
2.3:1
H
O
E
X
+
AcO
[Au]
O
·
AuL+
AuL+
G X = OAc
16
1,3-acetate
migration
X
O
O
+
F
[Au]
H X = OAc
H
X
X
[Au]
[Au]
1,2-acetate
migration
O
Acknowledgment
I X = OAc
26
H
X
We thank Miami University’s CFR and Shoupp programs for partial
support of this project. BWG is grateful for a NSF (1044549) TUES
grant. JW thanks GlaxoSmithKlein for a summer internship. Com-
putational modeling with Gaussian suite of programs was carried
out on the cluster computers of the Miami University Redhawk
High Performance Computing Center.
deauration
O
J X = OAc
Scheme 5 Proposed pathways for the observation of reactions of 12
producing two diastereoisomers and 16 producing only one diastereo-
mer
Financial support from the Shoupp and CFR programs of Miami
University is acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
computational coordinates and experimental procedures as well as
+
N
N
CN
NMR spectra.SunogIoiprfSmntranuIpgrfoi
m
p
nirtat
(IMes)Au(I)Cl
Au
N
AgSbF6, CH2Cl2
88%
29
References and Notes
Ph
–
SbF6
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Scheme 6 Preparation of PhCN-stabilized gold complex 30
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(27) General Procedure for the Au(I)-Catalyzed
Intramolecular [4+3]-Cycloadditions: To a round-bottom
flask equipped with a stirring bar under an atmosphere of
nitrogen were added AgSbF6 (2 mg, 0.007 mmol) and
IPrAuCl (0.007 mmol) in freshly distilled CH2Cl2 (0.5 mL)
and stirred for 5 min. The propargyl ester (0.07 mmol)
dissolved in freshly distilled CH2Cl2 (0.5 mL) was added
dropwise to the reaction and stirred at r.t. and monitored with
1H NMR. The reaction mixture was diluted with Et2O,
filtered through Celite, the solvent removed under reduced
pressure, and the residue purified over silica gel column.
[4+3]-Cycloaddition Product 26: 1H NMR (300 MHz,
CDCl3): δ = 0.97 (t, J = 7.35 Hz, 3 H), 1.04–1.20 (m, 1 H),
1.22–1.48 (m, 3 H), 1.68–1.89 (m, 4 H), 1.97 (d, J = 13.5 Hz,
1 H), 2.17 (s, 3 H), 2.43 (d, J = 17 Hz, 1 H), 2.89–2.92 (m, 1
H), 5.02 (d, J = 4.5 Hz, 1 H), 5.93 (d, J = 6.0 Hz, 1 H), 6.67
(d, J = 6.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 11.90,
18.83, 20.45, 23.27, 24.29, 29.70, 32.21, 42.05, 80.00,
83.42, 126.75, 129.47, 139.44, 141.89, 168.66. LCMS: m/z
[M + Na] calcd for C15H20O3: 271.1; found: 271.1.
[4+3]-Cycloaddition Product 27: 1H NMR (500 MHz,
CDCl3): δ = 1.24–1.46 (m, 4 H), 1.91–1.74 (m, 4 H), 1.99 (d,
J = 13.0 Hz, 1 H), 2.11 (s, 3 H), 2.20–2.11 (m, 2 H), 2.45 (d,
J = 14.5 Hz, 1 H), 3.05 (m, 1 H), 5.04 (m, 3 H), 5.81 (m, 1
H), 5.96 (d, J = 6.0 Hz, 1 H), 6.71 (d, J = 6.0 Hz, 1 H). 13
C
NMR (125 MHz, CDCl3): δ = 20.5, 23.2, 24.0, 24.4, 25.0,
31.4, 32.2, 39.9, 79.9, 83.4, 115.2, 126.6, 129.7, 137.8,
139.2, 142.0, 168.6. LCMS: m/z [M + Na] calcd for
C17H22O3: 297.1; found: 297.1.
Enyne Cyclization Product 28: 1H NMR (500 MHz,
CDCl3): δ = 0.75 (dd, J = 7.8, 5.4 Hz, 1 H), 1.04 (t, J = 4.8
Hz, 1 H), 1.10–1.38 (m, 2 H), 1.65–1.94 (m, 4 H), 2.04–2.06
(m, 2 H), 2.07 (s, 3 H), 2.14–2.25 (m, 1 H), 2.62 (t, J = 7.5
Hz, 2 H), 5.35 (d, J = 15.5 Hz, 1 H), 5.37–5.49 (m, 2 H), 5.98
(d, J = 3.0 Hz, 1 H), 6.29 (dd, J = 3.0, 1.8 Hz, 1 H), 7.31 (d,
J = 1.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 13.00,
21.25, 24.36, 26.02, 26.77, 27.34, 27.78, 31.99, 32.06,
78.24, 104.73, 110.03, 127.36, 131.80, 140.69, 156.21,
171.42. LCMS: m/z [M + Na] calcd for C17H22O3: 297.1;
found: 297.1.
Synlett 2013, 24, 1238–1242
© Georg Thieme Verlag Stuttgart · New York